This study aimed to investigate the effects of sustained hypoxic exposure on cerebral and muscle oxygenation and cardiorespiratory function at rest. Eleven healthy subjects inhaled a normobaric hypoxic () or normoxic () gas mixture for 4 h at rest, on two separated blinded sessions. Arterial oxygen saturation (), heart rate variability (HRV), end-tidal (), and oxygenation of quadriceps muscle, prefrontal and motor cortices assessed by near-infrared spectroscopy (NIRS) were measured continuously during each session. Acute mountain sickness symptoms were evaluated at the end of each session. During a hypoxic session, reduction () plateaued after 20 min, while deoxygenation pattern took 30 to 40 min at the cerebral sites to plateau ( of deoxygenated-hemoglobin). Deoxygenation was more pronounced in the cerebral cortex compared to the muscle ( of deoxygenated-hemoglobin), and NIRS-derived tissue perfusion index showed distinct profiles between the muscle (hypoperfusion) and the brain (hyperperfusion) with prolonged hypoxia. Changes in tissue oxygenation were not associated with cardiorespiratory responses (e.g., HRV, ) and altitude sickness symptom appearance during hypoxic sessions. These data demonstrate that sustained hypoxia elicits time delay in changes between arterial and tissue (especially cerebral) oxygenation, as well as a tissue-specific sensitivity.